The long-term objective of this research is to extend significantly the range of drugs for which transdermal delivery is a viable administration route. In particular, experiments are described to explore the potential of the skin as a systemic portal for new peptide and protein therapeutic agents emerging from the biotechnology industry. The focus of the proposal is to determine the feasibility and optimization of skin penetration enhancement by iontophoresis - the facilitation of (ionizable drug delivery across the skin by an applied electrical potential. The specific aims are to address the basic questions: By what mechanism(s) does iontophoresis enhance op iontophoresis dependent upon, and constrained by, penetrant properties? Iontophoresis concentrates attention on drug transport across the stratum corneum (SC, the outermost and least permeable skin layer) via "pores". The predominantly in vitro work proposed will: (a) use fluorescent probes and confocal microscopy to visualize routes of ionic flow across SC, (b) vectorize ionic transport with the vibrating probe electrode technique, (c) determine basic penetrant structure/properties-iontophoretic enhancement relationships, (d) develop the theoretical understanding of iontophoretic enhancement. Model penetrants for these experiments will be specifically designed peptide derivatives. Overall, a detailed examination of skin transport promotion by electrical means is outlined. In particular, the feasibility and optimization of peptide/small protein delivery, for which few acceptable alternatives exist, will be addressed.